Summary Neuroscience has an essential requirement for large-scale perturbation tools. Such tools would be transformative in the mapping of brain function, the causal testing of neurotheoretic models, and the diagnosis and treatment of neurological disorders. The proposed five-year project is aimed at uncovering the fundamental mechanisms of US stimulation through the reciprocity of mathematical analysis, computational modeling and experimental validation. Using a previously developed predicative model as a scaffold, we will build a full explanatory theory of US stimulation effects in mice, including cell-type specific effects of this perturbation modality. A large parameter space of US variables will be explored, including spatiotemporal dynamics and duty cycle modulation, while sensitive two-photon functional imaging metrics will be used to measure the biophysical impact of these parameters on neural responses in the cortex, thalamus, and hippocampus in vivo.